RU2379305C2 - Thiomorpholine compound and method for making thereof - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: there is described thiomorpholine compound presented by formula

(I) wherein the ring A represents benzene ring; the ring B represents benzene ring; R¹ represents hydrogen atom, R² represents C_1-6-alkyl group; R^3a and R^3b are identical or different, each representing hydrogen atom or C_1-6-alkyl group, and n represents an integer equal to 2, or its pharmaceutically acceptable salt. There is also described method for making the compound of formula (1), a pharmaceutical composition and application of the compound of formula (1) for making a medical product used for treatment and prevention of the disease chosen from inflammation, allergic diseases, pain, migraine, neuralgia, itch, cough, central nervous system diseases, alimentary organ diseases, nausea, vomiting and urological disorders.

EFFECT: compounds exhibits affinity to neurokinine-1 receptor.

6 cl, 4 tbl, 16 ex

Description

FIELD OF THE INVENTION

The present invention relates to a new thiomorpholine compound having excellent antagonistic activity against tachykinin receptors, and to the preparation of a piperidine compound.

State of the art

Tachycinin is the common name for the group of neuropeptides, and the substances P (hereinafter referred to as ″ SP ″), neurokinin-A and neurokinin-B in mammals are known. It is known that these peptides have different biological activity by binding to their corresponding receptors that exist in vivo (neurokinin-1, neurokinin-2, neurokinin-3). Among them, SP is one of the peptides that has been studied the longest and in detail. Its existence was confirmed by extracting the intestinal probe of a horse in 1931, and it is a peptide comprising 11 amino acids, the structure of which was determined in 1971.

SP is widespread in the central and peripheral nervous systems, and it has physiological activity, such as a vasodilating effect, improving vascular permeability, smooth muscle contraction, stimulation of neurons, salivary action, diuretic effect, immunological effect, etc., as well as neurotransmitter function primary sensory neuron. In particular, it is known that SP released from the terminal region of the horn of the spinal cord transmits pain information to the secondary sensory neuron during a pain impulse, and that SP released from the peripheral end causes an inflammatory response through its receptors. From these facts, it is believed that SP is involved in various diseases (for example, pain, inflammation, allergies, pollakiuria, urinary incontinence, respiratory disease, mental illness, depression, anxiety, vomiting, etc.), and, in addition, they consider that SP is involved in Alzheimer's type dementia [Review: Physiological Reviews, vol.73, pp.229-308 (1993) (Non-Patent Literature 1), Journal of Autonomic Pharmacology, vol.13, pp.23-93 (1993) ( Non-Patent Literature 2)].

Currently, as a compound having antagonistic activity for a tachykinin receptor, a compound represented by the following formula is described in WO 2003/011860:

in which R ¹ represents hydrogen or fluorine,

and a pharmaceutically acceptable acid addition salt thereof.

In addition, WO 2002/032867 describes a compound represented by the following formula:

in which R represents a halogen atom or a C _1-4 alkyl group;

R ₁ represents a C _1-4 alkyl group;

R ₂ represents hydrogen or a C _1-4 alkyl group;

R ₃ represents hydrogen or a C _1-4 alkyl group;

R ₄ represents a trifluoromethyl group;

R ₅ represents hydrogen, a C _1-4 alkyl group or a C (O) R ₆ ;

R ₆ represents C _1-4 alkyl, C _3-7 cycloalkyl, NH (C _1-4 alkyl) or N (C _1-4 alkyl) ₂ ;

m is 0 or an integer from 1 to 3;

n is an integer from 1 to 3,

or a pharmaceutically acceptable salt or solvated compound thereof.

WO 2003/066589 describes a compound represented by the formula:

wherein:

R represents halogen or C _1-4 alkyl;

R ₁ represents hydrogen or C _1-4 alkyl;

R ₂ represents hydrogen, C _1-4 alkyl, or R ₂ and R _{3 are} combined to form C _3-7 cycloalkyl;

R ₃ represents hydrogen, C _1-4 alkyl, C _3-7 cycloalkyl or C _3-6 alkenyl; or

R ₁ and R ₃ form a 5- or 6-membered heterocyclic group with nitrogen and carbon atoms with which they are combined;

R ₄ represents trifluoromethyl, C _1-4 alkyl, C _1-4 alkoxy, trifluoromethoxy or halogen;

R ₅ represents hydrogen, and R ₆ represents NR ₇ R ₈ , or R ₅ represents NR ₈ R ₉ and R ₆ represents hydrogen;

R ₇ represents hydrogen or C _1-4 alkyl, or R ₇ and R ₈ form a saturated 5-7 membered heterocyclic group containing oxygen, with nitrogen with which they are combined;

R ₈ represents hydrogen, phenyl, C _3-7 cycloalkyl, (CH ₂ ) _p C (O) NR ₁₀ R ₁₁ , a saturated 5-7 membered heterocyclic group (which may be substituted with C _1-4 alkyl, S (O ) ₂ C _1-4 alkyl or C (O) C _1-4 alkyl) containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, a 5-membered heteroaryl group (which may be substituted with C _1-4 alkyl, S (O) ₂ C _1-4 alkyl or C (O) C _1-4 alkyl) containing from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, or R ₈ represents a 6-membered heteroaryl group (which may be substituted with C _1-4 alkyl, S (O) ₂ C _1-4 al keel or C (O) C _1-4 alkyl) containing from 1 to 3 nitrogen atoms; or R ₈ represents a C _1-6 alkyl group which may optionally be substituted with 1 or 2 groups selected from fluorine, phenyl (which may be substituted with C _1-4 alkyl, C (O) C _1-4 alkyl or halogen) , = O, C _3-7 cycloalkyl, hydroxy, amino, dimethylamino, aminocarbonyl, C _1-4 alkoxy and trifluoromethyl;

R ₉ represents hydrogen or C _1-4 alkyl, or R ₉ and R ₈ may form a 5-7 membered heterocyclic group with the nitrogen to which they are attached, which may contain another heteroatom selected from oxygen, sulfur and nitrogen, and may be substituted with 1 or 2 groups selected from C _1-4 alkyl, = O, S (O) ₂ C _1-4 alkyl, C (O) C _3-7 cycloalkyl and C (O) C _1-4 alkyl;

R ₁₀ and R ₁₁ each independently represents hydrogen or a C _1-4 alkyl group,

X represents a nitrogen atom, and Y represents CH, or X represents CH, and Y represents a nitrogen atom;

m is 0 or an integer from 1 to 3;

n is an integer from 1 to 3,

p is 0, 1 or 2,

or a pharmaceutically acceptable salt or solvated compound thereof.

In addition, WO 2003/099787 describes a piperidine derivative represented by the formula:

wherein ring A is an optionally substituted benzene ring, ring B is an optionally substituted benzene ring, R ¹ is an optionally substituted alkyl group, an optionally substituted hydroxyl group, a substituted thiol group, a substituted carbonyl group, a substituted sulfinyl group, a substituted sulfonyl group, or a group represented by the formula:

R ¹¹ and R ¹² may be the same or different from each other, and each of them represents a hydrogen atom, a substituted carbonyl group, a substituted sulfonyl group, an optionally substituted alkyl group or a heterocyclic group containing from 1 to 4 atoms selected from a nitrogen atom , an oxygen atom and a sulfur atom as the heteroatom (s), wherein said heterocyclic group may be optionally substituted, and further, the nitrogen atom contained in said heterocyclic group may be oxidized , or it may be bonded at its ends to a neighboring nitrogen atom to form a heterocyclic group selected from a piperidino group, an azacycloheptyl group, a pyrrolidino group, an imidazolidinyl group, a hexahydropyrimidinyl group, a thiazolidyl group, a morpholino group, a triazolyl group, and an optionally tetrinol group may be substituted, and additionally, the nitrogen atom contained in said heterocyclic group may be oxidized, R ² pre represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom, Z represents an oxygen atom or a group represented by —N (R ³ ) -, R ³ represents a hydrogen atom or an optionally substituted alkyl a group, R ⁴ represents a hydrogen atom or an optionally substituted alkyl group, or a pharmaceutically acceptable salt thereof.

Description of the invention

Currently, as a therapeutic agent for the above various diseases (especially vomiting, depression, urological disorders, etc.), no compound has yet been found to have an excellent antagonistic effect on tachykinin receptors (specifically, an antagonistic effect on SP receptor) and having satisfactory safety and stability (metabolism, in vivo dynamics and absorption), etc. Therefore, a search was conducted for a compound having an excellent antagonistic effect on tachykinin receptors and having a sufficiently satisfactory clinical effect as a therapeutic agent.

The present invention relates to a thiomorpholine compound represented by the formula (I):

in which ring A is an optionally substituted benzene ring;

ring B is an optionally substituted benzene ring;

R ¹ represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom;

R ² represents a hydrogen atom or an optionally substituted alkyl group;

R ^3a and R ^3b may be the same or different from each other, and each of them represents a hydrogen atom or an optionally substituted alkyl group, or attached to each other at both ends to form an alkylene group, and

n is an integer equal to 1 or 2,

or a pharmaceutically acceptable salt thereof.

Effects of the invention

The present invention consists in providing a compound having an excellent antagonistic effect on tachykinin receptors and having a sufficiently satisfactory clinical effect, such as safety and stability (metabolism, in vivo dynamics and absorption), etc.

Preferred Embodiment

In the present invention, ring A is an optionally substituted benzene ring, and as the substituent (s) of the benzene ring, an alkyl group, a halogen atom, a cyano group, an optionally protected hydroxyl group or an alkoxy group can be mentioned. Ring A may have from 1 to 3 identical or different substituents selected from these substituents.

In the present invention, ring B is an optionally substituted benzene ring, and as a substituent (s) of the benzene ring, a trihaloalkyl group, a halogen atom, a cyano group, a phenyl group, a heterocyclic group containing from 1 to 4 heteroatoms selected from a nitrogen atom, can be mentioned oxygen and sulfur atom, an alkyl group, an optionally protected hydroxyl group or an alkoxy group. Ring B may have 1 to 3 identical or different substituents selected from these substituents.

As preferred examples of ring A and ring B in a compound of the present invention, a compound in which, for example, ring A is a benzene ring represented by the formula:

ring B is a benzene ring represented by the formula:

the substituents A ¹ , A ² and A ³ may be the same or different from each other, and each of them represents a hydrogen atom, a halogen atom, an alkyl group, an optionally protected hydroxyl group or an alkoxy group, B ¹ , B ² and B ³ may be identical or different from each other, and each of them represents a hydrogen atom, a trihaloalkyl group, a halogen atom, a cyano group, a phenyl group, a heterocyclic group containing from 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as a heteroat ma (s), an alkyl group, an optionally protected hydroxyl group or an alkoxy group. As the trihaloalkyl group, for example, a trifluoromethyl group or a trichloromethyl group, etc. can be mentioned. As a heterocyclic group containing from 1 to 4 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom as the heteroatom (s), for example, a tetrazolyl group can be mentioned.

In the present invention, as a protecting group for an optionally protected hydroxyl group, a commonly used protecting group can be mentioned, such as an optionally substituted arylalkyl group, an optionally substituted silyl group, an acyl group, etc. Of these groups, for example, an arylalkyl group such as a benzyl group, phenethyl group, etc .; a substituted silyl group such as a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, etc .; an acyl group such as a formyl group, acetyl group, propionyl group, malonyl group, acryloyl group, benzoyl group, etc.

In the present invention, R ¹ can be a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom.

In the present invention, an alkyl group may be indicated as a substituent of an optionally substituted hydroxyl group of R ¹ .

In the present invention, an alkyl group may be indicated as a substituent of an optionally substituted amino group R ¹ .

In the present invention, an alkoxy group may be indicated as a substituent of an optionally substituted alkyl group R ¹ .

In the present invention, a substituent of a substituted carbonyl group of R ¹ may be a hydroxyl group, an alkoxy group or an alkylamino group.

In the present invention, R ² can be a hydrogen atom or an optionally substituted alkyl group. As the substituent of the optionally substituted alkyl group R ^{2, there} may be mentioned a hydroxyl group, an alkanoyl group, a halogen atom, an alkoxy group or an alkylamino group.

In the present invention, R ^3a and R ^3b are the same or different from each other, and each of them is a hydrogen atom or an optionally substituted alkyl group, or a group that forms an alkylene group by linking the ends of R ^3a and R ^3b . As the substituent of an optionally substituted alkyl group, a hydroxyl group, etc. may be mentioned.

In the present invention, n can be indicated as an integer equal to 1 or 2.

As compound (I) of the present invention, a compound in which ring A is a benzene ring represented by the formula:

in which A ¹ represents an alkyl group, and A ² represents a halogen atom,

ring B is a benzene ring represented by the formula:

B ¹ represents a trihaloalkyl group, B ² represents a trihaloalkyl group, R ¹ represents a hydrogen atom, R ² represents an alkyl group, R ^3a and R ^3b may be the same or different from each other, and each of them represents a hydrogen atom or an alkyl group. In addition, as compound (I) of the present invention, a compound in which n is 2 is preferred.

In addition, of the compounds of the present invention, a compound selected from the following list of (a) to (g) or a pharmaceutically acceptable salt thereof is preferred.

(a) 1,1-dioxo-4- (S) - [1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R) - ( 4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,

(b) 1,1-dioxo-4- (R) - [1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R) - ( 4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,

(c) 1,1-dioxo-4- (S) - [1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R) - ( 4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,

(d) 1,1-dioxo-4- (R) - [1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R) - ( 4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,

(e) 1,1-dioxo-4- (S) - [1- {N- (3,5-bistrifluoromethylphenyl) methyl-N-methyl} -2- (R) - (4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,

(f) 1,1-dioxo-4- (R) - [1- {N- (3,5-bistrifluoromethylphenyl) methyl-N-methyl} -2- (R) - (4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine and

(g) 4- (S) - [1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R) - (4-fluoro-2- methylphenyl) aminocarbonylpiperidin-4-yl] -1-oxothiomorpholine.

Compound (I) of the present invention can be used for pharmaceutical purposes either in free form or in the form of a pharmaceutically acceptable salt.

As the pharmaceutically acceptable salt of compound (I) of the present invention, for example, an inorganic acid salt such as hydrochloride, sulfate, phosphate and hydrobromide; and an organic acid salt such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, maleate, succinate and tartrate.

In addition, the compound (I) of the present invention or a pharmaceutically acceptable salt thereof includes any internal salt, solvate and hydrate thereof, etc.

Although an asymmetric carbon atom optical isomer may be present in compound (I) of the present invention, the present invention includes any of these optical isomers and mixtures thereof. In the present invention, among these optical isomers, a compound having an R configuration in the 2-position of the piperidine ring (connecting the position of ring A) is preferred.

Compound (I) or a pharmaceutically acceptable salt thereof of the present invention has an excellent antagonistic effect on tachykinin receptors, in particular an antagonistic effect on the SP receptor, as a result of which it is applicable as a safe drug for the prevention and treatment of inflammation or allergic diseases (e.g., atopic dermatitis, dermatitis, herpes, psoriasis, asthma, bronchitis, sputum production, rhinitis, rheumatoid arthritis, osteoarthritis, osteoporosis, multiple sclerosis erosion, conjunctivitis, ophthalmia, cystitis, etc.), pain, migraine, neuralgia, pruritus, cough and, in addition, diseases of the central nervous system (e.g. schizophrenia, Parkinson's disease, depression, anxiety, psychosomatic disorder, morphine addiction, dementia (e.g., Alzheimer's disease, etc.), etc.), digestive diseases (e.g., irritable bowel syndrome, ulcerative colitis, Crohn's disease, upsets (e.g., gastritis, stomach ulcers, etc.), related to urease-positive Spirillum (e.g. helicobacter pylori , etc. ), etc.), nausea, vomiting, urological disorder (e.g. pollakiuria, involuntary urination, etc.), circulatory disease (e.g., angina pectoris, hypertension, heart failure, thrombosis, etc.) and immune disorders, etc. in mammals (e.g., mouse, guinea pig, clawed Mongolian gerbil, ferret, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human, etc.). In particular, since compound (I) or a pharmaceutically acceptable salt thereof, which are the active ingredient of the present invention, has high penetration into the brain and has low toxicity (high safety), showing an almost complete absence of side effects, it is applicable as a therapeutic or prophylactic agents for diseases of the central nervous system, such as vomiting, depression and the like, or a urological disorder such as pollakiuria, etc.

Measurements with a compound of the present invention or a pharmaceutically acceptable salt thereof can be carried out by the method described in European Journal of Pharmacology, vol. 254, pp. 221-227 (1994) regarding the binding action of the neurokinin-1 receptor, according to the method described in European Journal of Pharmacology, vol. 265, pp. 179-183 (1994) regarding the antagonistic effect on the neurokinin-1 receptor, and by the method described in Journal of Urology, vol. 155, No. 1, pp. 355-360 (1996) regarding the inhibitory effect on pollakiuria.

Compound (I) or a pharmaceutically acceptable salt thereof of the present invention can be administered orally or parenterally, and a suitable formulation can be formulated using a conventional pharmaceutical carrier for oral or parenteral administration. As such a pharmaceutical carrier, for example, a binder (syrup, Arabian gum, gelatin, sorbitol, tragacanth gum, polyvinylpyrrolidone, etc.), a filler (lactose, sugar, corn starch, potassium phosphate, sorbitol, glycine and t etc.), a lubricant (magnesium stearate, talc, polyethylene glycol, silicon dioxide, etc.), a substance that promotes the disintegration of the dosage form (potato starch, etc.) and a moisturizer (anhydrous sodium lauryl sulfate, etc. .) and similar. In addition, when these pharmaceutical preparations are administered orally, they may be a solid preparation, such as tablets, granules, capsules and powders, or a liquid preparation, such as a solution, suspension and emulsion. On the other hand, when they are administered parenterally, they can be administered, for example, as an injection solution or an infusion solution using distilled water for injection, physiological saline solution, aqueous glucose solution, etc., or they can be administered as a suppository and a similar dosage form.

The dose of compound (I) or a pharmaceutically acceptable salt thereof of the present invention may vary depending on the method of administration, age, body weight or condition of the patient, etc., and, for example, in the case of oral administration, the administered dose is usually from 0.01 up to 20 mg / kg per day, and particularly preferably from 0.01 to 10 mg / kg per day, and in the case of parenteral administration, the dose is usually from 0.01 to 10 mg / kg per day, particularly preferably from 0, 01 to 1 mg / kg per day.

[Method A]

A preferred compound (I) of the present invention can be obtained, for example, by reacting a compound represented by formula (II):

in which ring A is an optionally substituted benzene ring;

ring B is an optionally substituted benzene ring;

R ¹ represents a hydrogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted alkyl group, a substituted carbonyl group or a halogen atom;

R ² represents a hydrogen atom or an optionally substituted alkyl group; and

R ^3a and R ^3b may be the same or different from each other, and each of them represents a hydrogen atom or an optionally substituted alkyl group, or a group that forms an alkylene group at its ends,

in the presence of an oxidizing agent.

[Method B]

A preferred compound (I) of the present invention can be obtained, for example, by reacting a compound represented by formula (III):

in which the ring A, R ¹ and n have the same meanings as defined above,

with the compound represented by formula (IV):

in which the ring B, R ² , R ^3a and R ^3b have the same meanings as defined above,

in the presence of a urea bond reagent.

[Method C]

A preferred compound (I) of the present invention can be obtained, for example, by reacting a compound represented by formula (V) or a salt thereof:

in which ring A, ring B, R ¹ , R ² , R ^3a and R ^3b have the same meanings as defined above,

with the compound represented by formula (VI):

in which n has the same meaning as defined above, in the presence of a base.

These methods [method A] - [method C] can be implemented as follows.

[Method A]

This preparation method can be carried out by reacting compound (II) in the presence of an oxidizing agent in a suitable solvent. As an oxidizing agent, there can be mentioned, for example, 3-chloroperbenzoic acid, peracetic acid, sodium periodate, OXONE, etc. In addition, any solvent can be used as a solvent, provided that it does not have any harmful effect on the reaction, and, for example, dichloromethane, chloroform, acetonitrile, dimethoxyethane, tetrahydrofuran, water, etc. can be optionally used. This reaction can be carried out, for example, at a temperature of from -80 ° C to 150 ° C, preferably from 0 ° C to 50 ° C.

[Method B]

The reaction of compound (III) with compound (IV) can be carried out in the presence of a urea bond forming compound in a suitable solvent. As the compound forming the urea bond, here you can specify the compound represented by the formula:

in which the groups W ¹ and W ² may be the same or different from each other, and each of them represents a leaving group.

W ¹ and W ² may be the same or different from each other, and each of them may be an imidazolyl group, a halogen atom or a phenoxy group. Specifically, 1,1'-carbonyldiimidazole, phosgene, etc. are preferred, and for example, carbonyldihalide such as 1,1'-carbonyldiimidazole, triphosgene or phosgene, etc. can be used. In addition, any solvent can be used as a solvent, provided that it does not have any harmful effect on the reaction, and, for example, acetonitrile, dichloromethane, tetrahydrofuran, etc. can optionally be used. This reaction can be carried out, for example, at a temperature of from 0 ° C to 80 ° C, preferably from 0 ° C to 50 ° C.

Moreover, this reaction can be carried out by reacting compound (III) with a urea bond forming compound represented by the formula:

in which the groups W ¹ and W ² have the same meanings as defined above,

obtaining the compound represented by formula (VII):

in which the ring A, R ¹ , W ² and n have the same meanings as defined above,

then the compound (VII) is converted into its reactive derivative, and it is reacted with the compound (IV), or the compound (IV) is reacted with a urea bond forming compound represented by the formula:

in which W ¹ and W ² have the same meanings as defined above,

obtaining the compound represented by formula (VIII):

in which the ring B, R ² , R ^3a , R ^3b and W ² have the same meanings as defined above,

then the compound (VIII) is converted into its reactive derivative and reacted with the compound (III) to obtain the compound (I).

As reactive derivatives, for example, in compound (VII) or compound (VIII), a compound in which W ^{2 is} converted to the group represented by the formula:

The interaction between compound (III) or compound (IV) and a urea bond forming reagent can be carried out, for example, at a temperature of from 0 ° C to 80 ° C, preferably from 0 ° C to 50 ° C. In addition, any solvent can be used as a solvent, provided that it does not have any harmful effect on the reaction, and, for example, acetonitrile, dichloromethane, tetrahydrofuran, etc. can optionally be used.

The reaction that converts compound (VII) or compound (VIII) into their reactive derivatives can be carried out, for example, using a reactive derivative-producing reagent, such as methyl iodide, at a temperature of from 0 ° C to 80 ° C, preferably from 0 ° C to 50 ° C. In addition, any solvent can be used as a solvent, provided that it does not have any harmful effect on the reaction, and optionally, for example, acetonitrile, dichloromethane, tetrahydrofuran, etc. can be used.

The interaction of the corresponding reactive derivatives and compound (III) or compound (IV) can be carried out, for example, in the presence of a base at a temperature of from 0 ° C to 80 ° C, preferably from 0 ° C to 50 ° C. In addition, any substance can be used as a base, for example triethylamine, etc., and any substance can be used as a solvent, provided that it does not have any harmful effect on the reaction and, for example, toluene can optionally be used, acetonitrile, dichloromethane, tetrahydrofuran, etc.

[Method C]

The interaction of compound (V) and compound (VI) can be carried out in the presence of a base in a suitable solvent. As the base, for example, an organic base such as triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 1,8-diazabicyclo- [5.4.0] undec-7-ene, etc., or an inorganic base can be mentioned. such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tert-butoxide, etc. In addition, any solvent may be used as a solvent, provided that it does not adversely affect the reaction, and optionally, for example, methanol, ethanol, isopropanol, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, ethyl acetate, toluene, etc. or a mixed solvent, or a mixture of solvents, or a mixed solvent and water. As the salt of compound (V), for example, an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, etc., and an organic acid salt such as methanesulfonate, p-toluenesulfonate, acetate, carbonate, trifluoroacetate, etc. can be mentioned. d. This reaction can be carried out, for example, at a temperature of from 10 ° C to a reflux temperature, preferably from 50 ° C to 120 ° C.

In particular, the compound represented by formula (IX):

in which ring A, ring B, R ¹ , R ² , R ^3a and R ^3b have the same meanings as defined above,

or its optical isomer can be prepared by the method described in WO 2003/099787.

Compound (II) can be prepared by subjecting a mixture of compound (IX) or its salt and thiomorpholine in a suitable solvent to reductive amination. This reductive amination can be carried out under acidic conditions by hydrogenation with a reducing agent such as sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, etc., or a reducing catalyst, such as palladium, etc. As the solvent, any solvent may be used provided that it does not adversely affect the reaction, and optionally, for example, dichloromethane, acetic acid, ethanol, methanol, etc. can be used. Optionally, hydrochloride, acetate, etc. may be used as a salt of compound (IX). This reaction can be carried out, for example, at a temperature of from -10 ° C to 80 ° C, preferably from 0 ° C to 30 ° C.

In addition, the compound represented by formula (X):

in which R ⁴ represents a hydrogen atom or a protective group for an amino group, ring A and R ¹ have the same meanings as defined above,

or its optical isomer can be prepared by the method described in WO 2002/032867.

As the protecting group for the amino group R ⁴ , an alkoxycarbonyl group, such as a tert-butoxycarbonyl group, etc., and an arylalkoxycarbonyl group, such as a benzyloxycarbonyl group, etc. can be mentioned.

Compound (III) can be prepared by subjecting a mixture of compound (X) or a salt thereof and thiomorpholine to reductive amination in a suitable solvent, and when R ⁴ is a protecting group for an amino group, the protecting group is then removed. Reductive amination can be carried out under acidic conditions by hydrogenation with a reducing agent such as sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, etc., or a reducing catalyst, such as palladium, etc. As the solvent, any solvent can be used provided that it does not adversely affect the reaction, and optionally, for example, dichloromethane, acetic acid, ethanol, methanol, etc. can be used. Optionally, hydrochloride, acetate, etc. may be used as a salt of compound (X). This reaction can be carried out, for example, at a temperature of from -10 ° C to 80 ° C, preferably from 0 ° C to 30 ° C. In addition, the deprotection of an amino group can be carried out in a conventional manner.

In addition, the compound represented by formula (XI):

in which ring A, ring B, R ¹ , R ² , R ^3a and R ^3b have the same meanings as defined above,

or its optical isomer can be prepared by the method described in WO 2003/099787.

The compound represented by formula (XII):

in which ring A, ring B, R ¹ , R ² , R ^3a and R ^3b have the same meanings as defined above,

or its optical isomer can be prepared by the method described in WO 2003/099787.

In addition, compound (III) can be prepared in the same manner as above method C, for example, by reacting a compound represented by formula (XIII) or a salt thereof:

in which the ring A, R ¹ , and R ⁴ have the same meanings as defined above,

and compounds represented by formula (VI):

in which n has the same meanings as defined above, in the presence of a base, and then removing the amino protecting group (R ⁴ ), if desired.

In addition, to obtain the desired compounds and starting compounds of the present invention, when the starting compounds or the corresponding intermediates have a functional group (s), a suitable protecting group is introduced into the corresponding functional group (s) by traditional methods of synthetic chemistry other than those indicated above, and if they are not necessary, these protecting groups can optionally be removed.

In the present description, an alkyl group means, for example, a straight or branched chain alkyl group containing from 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, isopentyl group, etc., preferably, groups containing from 1 to 4 carbon atoms. An alkenyl group means, for example, a straight or branched chain alkenyl group containing from 2 to 7 carbon atoms, such as a vinyl group, an allyl group, a propenyl group, an isopropenyl group, etc., preferably, groups containing from 2 to 5 carbon atoms. An alkoxy group means, for example, a straight or branched chain alkoxy group containing from 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, etc., preferably, groups containing from 1 to 4 carbon atoms. An alkanoyl group means, for example, a straight or branched chain alkanoyl group containing from 1 to 6 carbon atoms, such as formyl group, acetyl group, propionyl group, butyryl group, valeryl group, tert-butylcarbonyl group, etc., preferably groups containing from 1 to 4 carbon atoms. A cycloalkyl group means, for example, a cycloalkyl group containing from 3 to 8 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, etc., preferably, groups containing from 3 to 6 carbon atoms. In addition, halogen atoms are illustrated by a chlorine atom, a bromine atom, a fluorine atom or an iodine atom.

[Example]

Example 1

To 2 ml of a dichloromethane solution containing 90 mg of 4- (S) - [1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R) - ( 4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine, 0.02 ml of methanesulfonic acid and 105 mg of meta-chloroperbenzoic acid were added and the mixture was stirred at room temperature for 3 hours. An aqueous solution of sodium thiosulfate was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 30 minutes. Water and chloroform were added to the mixture, the liquids were separated, and the aqueous layer was again extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) and then column chromatography on silica gel (chloroform: ethyl acetate = 3: 1) to obtain 44 mg of 1,1-dioxo-4- (S) - [1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R) - (4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine shown in the following table 1.

Examples 2-6

Using the appropriate starting materials, the same procedures were carried out as in Example 1, to obtain the compounds shown in the following Tables 1 and 2.

Example 7

To 5 ml of a dichloromethane solution containing 80 mg of 4- (S) - [1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R) - ( 4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine, 0.034 ml of 4M hydrochloric acid (solution in 1,4-dioxane) was added dropwise, then 33 mg of meta-chloroperbenzoic acid (70%) was added to this mixture at -10 ° C and the resulting mixture was stirred for one hour. An aqueous solution of sodium bicarbonate and dichloromethane were added to the reaction mixture, and then the liquids were separated. The resulting organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 19: 1). The product was lyophilized with tert-butanol to give 50 mg of 4- (S) - [1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R) - ( 4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] -1-oxothiomorpholine shown in the following table 2.

Example 8

To 15 ml of a solution of 1,4-dioxane containing 11.3 g of (2R, 4S) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4 tert-butoxycarbonylamino-2- (4-fluoro-2-methylphenyl) piperidine, 45 ml of 4M hydrochloric acid (solution in 1,4-dioxane) was added dropwise and the resulting mixture was stirred for two hours at room temperature. The solvent was removed under reduced pressure and the residue was dried under vacuum. To 50 ml of an ethanol solution containing this residue, 3 g of divinyl sulfone and 5.1 g of triethylamine were added, and the resulting mixture was stirred for two and a half hours at the boil under reflux. The solvent was removed under reduced pressure and the residue was crystallized from diisopropyl ether to give 10.3 g of the same compound as in Example 1 above.

Comparative Example 1

To 60 ml of a tetrahydrofuran solution containing 3.91 g of N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methylamine, 2.34 g of 1,1'-carbonyldiimidazole was added and the mixture was stirred at 40 ° C during the night. After distilling off the solvent from the reaction mixture, ethyl acetate was added to the residue, and all organic layers were washed with water and brine, dried, and the solvent was distilled off. The residue was crystallized from diisopropyl ether and collected by filtration. The obtained white crystals were dissolved in 60 ml of acetonitrile, then 3.4 ml of methyl iodide was added to the solution, the mixture was reacted at 60 ° C for 2 hours, and the solvent was distilled off. The residue was dissolved in 40 ml of dichloromethane and, while cooling in an ice bath, 3.47 g of 2- (4-fluoro-2-methylphenyl) -4,4-dimethoxypiperidine and 3.82 ml of triethylamine were added to the solution, and the mixture was stirred at room temperature for nights. The reaction mixture was poured into water, the liquids were separated, and the aqueous layer was extracted with dichloromethane. All organic layers were washed with water and brine, dried and the solvent was distilled off. The residue was dissolved in 90 ml of tetrahydrofuran, while cooling in an ice bath, 30 ml of a 1M aqueous solution of sulfuric acid was added to the solution, and the mixture was stirred at room temperature for 5 hours. After adjusting the pH of the mixture to 8-9 using a 1M aqueous solution of sodium hydroxide, tetrahydrofuran was distilled off, water and ethyl acetate were added to the residue, and the liquids were separated, and the aqueous layer was extracted again with ethyl acetate. All organic layers were washed with water and brine, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 2.12 g (2R) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl ] aminocarbonyl-2- (4-fluoro-2-methylphenyl) -4-oxopiperidine shown in the following table 3.

Comparative Examples 2 and 3

Using the appropriate starting materials, the same procedures were carried out as in comparative example 1, obtaining the compounds shown in the following table 3.

Reference Example 4

To 15 ml of a dichloromethane solution containing 504 mg of (2R) -1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-2- (4-fluoro-2- methylphenyl) -4-oxopiperidine, 155 mg of thiomorpholine and 0.057 ml of acetic acid, 446 mg of sodium triacetoxyborohydride was added and the mixture was stirred at room temperature for 16 hours. To the reaction mixture were added 52 mg of thiomorpholine and 112 mg of sodium triacetoxyborohydride and the mixture was further stirred at room temperature for 3 hours. Water and chloroform were added to the mixture, the liquids were separated, and the aqueous layer was again extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic column chromatography on silica gel (n-hexane: ethyl acetate = 3: 1) and then column chromatography on silica gel (chloroform: ethyl acetate = 3: 1) to obtain 92 mg (a) 4- (S) - [2- (R) - (4-fluoro-2-methylphenyl) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonylpiperidin-4-yl] thiomorpholine and 164 mg (b) 4- (R) - [2- (R) - (4-fluoro-2-methylphenyl) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N- methyl] aminocarbonylpiperidin-4-yl] thiomorpholine shown in the following table 3.

Comparative Examples 5 and 6

Using the appropriate starting materials, the same procedures were carried out as in comparative example 4, obtaining the compounds shown in the following table 4.

Reference Example 7

To a solution of N, N-dimethylformamide containing 280 mg (2R, 4R) -1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] aminocarbonyl-4-bromo-2 - (4-fluoro-2-methylphenyl) piperidine, 0.2 ml of thiomorpholine was added and the mixture was stirred at 90 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 3) to obtain 80 mg of the same compound as in the above comparative example 4 (a).

Table 1

table 2

Table 3

Table 4

Industrial Applicability of the Invention

The compounds of the present invention have an excellent antagonistic effect on tachykinin receptors. In addition, the compounds of the present invention are highly safe and excellent in terms of absorption, brain penetration, metabolic stability, blood concentration, resistance, etc. and thus have excellent medical effects.

Example 9

According to the method described in European Journal of Pharmacology, Volume 254, pp. 212-227 (1994), IM-9 cells (4 × 10 ⁶ cells in vitro) together with 0.3 nM [ ³ H] (Sar ⁹ , Met ¹¹ (O ₂ )) substances P (constant Kd = 0.17 nM) and 10 nM of the test substance were incubated in 0.5 ml of 50 mM Tris-HCl (pH 7.4, 25 ° С) containing 150 mM NaCl , 3 mM MnCl ₂ , 40 μg / ml bacitracin, 4 μg / ml leupeptin, 4 μg / ml chymostatin, 4 μg / ml phospholamidone and 0.02% bovine serum albumin, at room temperature for 60 minutes. After incubation, the cells were collected by vacuum filtration through a GF / C glass filter pretreated with 0.3% polyethyleneamine. Cells were washed twice with 3 ml of ice-cold reagent buffer in the absence of bovine serum albumin and various protease inhibitors. The radioactivity (dpm = half-life per minute) of the filter was determined using a liquid scintillation counter. The exact binding amount was determined by subtracting the non-specific binding amount (neurokinin-1 receptor antagonist L-703606, 2 μl) from the total binding amount. The degree of inhibition of the test compound (10 nM) was calculated by the binding specificity of the labeled ligand.

The results of the study are shown in table 5.

Table 5. Measurement number The degree of inhibition (%) one 89 2 86 3 78 four 64 5 94 6 75

Example 10

Getting pills.

A 180 mg tablet was prepared according to standard technology using components 1-6, as described below.

Ingredient Amount (mg) 1. the compound of example 1 40 2. lactose 38 3. hydroxypropyl cellulose 2 4. cross-linked sodium carboxymethyl cellulose 9 5. DILACTOSE® 89.2 6. magnesium stearate 1.8

Claims (6)

1. The compound of thiomorpholine represented by formula (I)

in which ring A represents a benzene ring represented by the formula

in which A ¹ represents a C _1-6 alkyl group, and A ² represents a halogen atom,
ring B is a benzene ring represented by the formula

,
in which B ¹ represents a trihalo-C _1-6 alkyl group, and B ² represents a trihalo-C _1-6 alkyl group,
R ¹ represents a hydrogen atom, R ² represents a C _1-6 alkyl group, R ^3a and R ^3b are the same or different from each other, and each of them represents a hydrogen atom or a C _1-6 alkyl group and
n is an integer equal to 2,
or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, selected from the following list from (a) to (f):
(a) 1,1-dioxo-4- (S) - [1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R) - ( 4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,
(b) 1,1-dioxo-4- (R) - [1- [N- {1- (R) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R) - ( 4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,
(c) 1,1-dioxo-4- (S) - [1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R) - ( 4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,
(d) 1,1-dioxo-4- (R) - [1- [N- {1- (S) - (3,5-bistrifluoromethylphenyl) ethyl} -N-methyl] -2- (R) - ( 4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,
(e) 1,1-dioxo-4- (S) - [1- {N- (3,5-bistrifluoromethylphenyl) methyl-N-methyl} -2- (R) - (4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine,
(f) 1,1-dioxo-4- (R) - [1- {N- (3,5-bistrifluoromethylphenyl) methyl-N-methyl} -2- (R) - (4-fluoro-2-methylphenyl) aminocarbonylpiperidin-4-yl] thiomorpholine or a pharmaceutically acceptable salt thereof. 3. A method of obtaining a compound of thiomorpholine represented by formula (I)

in which ring A represents a benzene ring represented by the formula

in which A ¹ represents a C _1-6 alkyl group, and A ² represents a halogen atom,
ring B is a benzene ring represented by the formula

,
in which B ¹ represents a trihalo-C _1-6 alkyl group, and B ² represents a trihalo-C _1-6 alkyl group,
R ¹ represents a hydrogen atom, R ² represents a C _1-6 alkyl group, R ^3a and R ^3b are the same or different from each other, and each of them represents a hydrogen atom or a C _1-6 alkyl group and
n is an integer equal to 2,
or its pharmaceutically acceptable salt,
which includes the interaction of the compounds represented by formula (II)

in which ring A, ring B, R ¹ , R ² , R ^3a and R ^3b have the same meanings as defined above,
in the presence of an oxidizing agent, and then converting the product into its pharmaceutically acceptable salt, if desired. 4. A pharmaceutical composition for treating and preventing a disease selected from inflammation, allergic diseases, pain, migraine, neuralgia, pruritus, cough, diseases of the central nervous system, diseases of the digestive system, nausea, vomiting, urological disorder, comprising a compound according to any one of paragraphs. 1 or 2, in a clinically effective amount and a pharmaceutically acceptable carrier. 5. The use of a compound according to any one of claims 1 or 2 for the preparation of a medicament for the treatment and prevention of a disease selected from inflammation, allergic diseases, pain, migraine, neuralgia, pruritus, cough, diseases of the central nervous system, diseases of the digestive system, nausea, vomiting, urological disorder. 6. The use according to claim 5, in which the disease is a urological disorder.